Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-2 (IL-2) belongs to a class of soluble, regulatory proteins known as cytokines. It is a 133 amino acid glycoprotein secreted by T(H) lymphocytes and other cells following activation by antigens, mitogens and other cytokines. It stimulates the proliferation and cytotoxicity of T lymphocytes. It also enhances the microbicidal and cytotoxic activities of NK cells, B lymphocytes, macrophages and monocytes. IL-2 can now be produced in unlimited quantities by recombinant DNA technology and used therapeutically to modulate the immune system in a number of diseases. A number of different studies have demonstrated its therapeutic value in HIV +ve and AIDS patients. It has been approved by US-FDA for treatment of metastatic renal cell carcinoma (RCC) and metastatic melanoma. Routine detection of soluble IL-2 receptor in blood could be useful as a diagnostic marker in some autoimmune diseases. Agents that antagonize IL-2 find application as immunosuppressants. The main adverse effect of IL-2 is capillary leak syndrome caused by increased capillary permeability and extravasation of fluid. In days to come, IL-2 is likely to play an increasingly important role in management of viral infections, malignancies and a number of other diseases conditions.
 ...
PMID:Interleukin-2 as a therapeutic agent. 1183 57

The noncytotoxic soluble factor produced by CD8+ T cells inhibits replication of HIV and SIV in vitro and is thought to play a crucial role in combatting infection in vivo. We determined the effect of human CD8+ lymphocytes on the in vitro replication potential of both wild-type and nef-defective mutants of the simian immunodeficiency virus SIVmac251. Although replication of wild-type SIVmac251 in unstimulated human PBMC supplemented with IL-2 was unaffected by the presence of CD8+ T cells, the nef mutants were susceptible to the inhibitory effects. The effect of exogenous IL-2 depended upon the culture conditions: (i) in nonstimulated human PBMC depleted of CD8+ T cells, addition of IL-2 had a positive effect on the growth of the nef-defective viruses; (ii) in total human PBMC, IL-2 appeared to reinforce the CD8+ T-cell-dependent inhibition of the same mutant viruses. This strongly suggests that IL-2 stimulates the noncytotoxic anti-HIV/SIV response of CD8+ cells present in PBMC cultures. PHA stimulation of unfractionated human PBMC overrode the suppression of viral replication by CD8+ T cells. Depletion of activated T cells expressing the IL-2 receptor alpha-chain (CD25+ T cells), present in small amounts in these primary T cell cultures, dramatically reduced viral replication, indicating that the depleted cell population harbors the target cells permissive for viral replication. Furthermore, using neutralizing antibodies we could show that inhibition by the beta-chemokines MIP-1alpha, MIP-1beta, and RANTES and the inhibitory effect of CD8+ lymphocytes on nef mutant SIVmac viruses are harbored on different levels.
 ...
PMID:Simian immunodeficiency viruses with defective nef genes show increased susceptibility to the noncytotoxic antiviral activity of CD8+ lymphocytes. 1188 79

Interleukin-2 (IL-2) is a T cell derived cytokine that leads to a sustained expansion of the CD4+ T cell pool when given as 5-day cycles approximately every 8 weeks. An extensive series of phase I/II studies have been carried out and have leaded to the initiation of two phase III trials that are currently enrolling patients in 23 countries. Studies of the mechanisms of action have revealed that IL-2 is capable of inducing the polyclonal proliferation of CD4+ and CD8+ T cells, even in the absence of expression of the high affinity IL-2 receptor. While IL-2 leads to a 6-fold increase in T cell proliferation and a 2-fold increase in T cell death, the primary mechanism of action leading to expansion of the CD4+ T cell pool appears to be an increase in CD4+ T cell survival. While early work focused on the ability of IL-2 to exert these effects in patients with relatively early stages of HIV infection, more recent work, in the setting of HAART, indicates that these effects may be seen at all stages of HIV disease. The results of the phase III studies should provide an answer to the question of whether or not this is a strategy that will be of clinical benefit.
 ...
PMID:The potential role of interleukin-2 in patients with HIV infection. 1199 83

HIV-infected individuals with 200-500 CD4(+) T cell/microl were enrolled in a controlled study of three interleukin 2 (IL-2) plus antiretroviral therapy (ART) regimens: (1) continuous intravenous administration of 12 million international units (MIU) of IL-2 followed by subcutaneous high-dose IL-2 (7.5 MIU, twice daily) for 5 days every 8 weeks; (2) high-dose subcutaneous IL-2 for 5 days every 8 weeks; (3) low-dose (3 MIU, twice daily) subcutaneous IL-2 for 5 days every 4 weeks; and (4) ART alone. Serum concentrations of IL-2, soluble IL-2 receptor (sIL-2R), tumor necrosis factor alpha (TNF-alpha), and IL-6 were determined. A progressive decrease over time of the circulating levels of IL-2 was observed in individuals receiving the highest doses of IL-2, but not in those belonging to the low-dose arm. Conversely, increased levels of sIL-2R were observed in all cytokine-treated individuals. The levels of TNF-alpha increased in the high-dose IL-2 regimens, but decreased in individuals receiving low-dose IL-2. IL-2-related toxicity was significantly correlated to the peak IL-2 serum levels, and was substantially lower in those individuals receiving low-dose IL-2. In conclusion, intermittent IL-2 administration causes the elevation of peripheral CD4(+) T cells, but also a profound cytokine response and systemic toxicity. The latter was correlated to the peak serum level of IL-2, but not to those of TNF-alpha and IL-6.
 ...
PMID:Tumor necrosis factor alpha, interleukin 2, and soluble interleukin 2 receptor levels in human immunodeficiency virus type 1-infected individuals receiving intermittent cycles of interleukin 2. 1201 2

Forty-four patients with chronic HBV and HCV were observed. Serum levels of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and soluble IL-2 receptor (IL-2r) were measured by enzyme immunoassay in 29 patients divided into 3 groups: group 1 (n = 9) with chronic HBV, group 2 (n = 9) with chronic HCV, and group 3 (n = 11) with mixed HBV + HCV infection. Control group consisted of 10 normal subjects without HBV, HCV, or HIV infection markers. The most informative of Th1 cytokines was IL-2r: its concentration was increased significantly (p < 0.01) in all patients with hepatitis B and/or C in comparison with the control. In addition, there was a trend to an increase in the mean concentrations of IL-2r from group 1 to groups 2 and 3. The concentrations of IFH-gamma and IL-2 did not differ significantly in the patients and controls. However, the concentrations of IFN-gamma were increased significantly (p < 0.01) in comparison with the control in 3 patients from group 1 and 4 patients from group 3 with more pronounced inflammation.
 ...
PMID:[Th1-cytokines in chronic hepatitis B and C]. 1217 30

The long-term immunologic effects of intermittent interleukin 2 (IL-2) therapy were evaluated in a cross-sectional study by comparing 3 groups: HIV-seronegative volunteers, HIV-infected (HIV(+)) patients receiving highly active antiretroviral therapy (HAART), and HIV(+) patients receiving HAART and intermittent IL-2. Whole-blood immunophenotyping was performed to study expression of the IL-2 receptor chains on T lymphocytes and natural killer cells and to further characterize CD4(+)/CD25(+) T cells. Increased CD25 expression, especially in CD4(+) T cells but also in CD8(+) T cells, without increases in expression of the beta and gamma chains of the IL-2 receptor was detected in the IL-2 group. Up to 79% of naive CD4(+) T cells (median, 61%) from patients in the IL-2 group expressed CD25, and the number of naive CD4(+)/CD25(+) T cells correlated positively with both the total and naive CD4(+) T-cell counts. A discrete population of CD45 double intermediate RA(+)/RO(+) CD4(+) cells was also preferentially expanded in the IL-2 group, and the number of these cells strongly correlated with the total CD4(+) count. Despite increases in CD25 expression, T lymphocytes from patients treated with IL-2 did not have increased expression of early (CD69) or late (CD95) activation markers or evidence of recent proliferation (Ki67). Both CD4(+)/CD25(+) and CD4(+)/CD25(-) cells from IL-2-treated HIV(+) patients proliferated in response to mitogens, specific antigens, and T-cell-receptor-mediated stimuli. Thus, intermittent administration of IL-2 in HIV(+) patients leads to preferential expansion of a unique subset of CD4(+) T cells that may represent a critical population in T-cell homeostasis.
 ...
PMID:Long-term effects of intermittent interleukin 2 therapy in patients with HIV infection: characterization of a novel subset of CD4(+)/CD25(+) T cells. 1220 Mar 81

A recombinant human IL-2 analog (rIL-2, Proleukin) is currently being evaluated for clinical benefit in HIV infected patients. It is approved for therapy of patients with metastatic melanoma and renal cell carcinoma. Treatment of cancer patients with rIL-2 results in durable responses but is associated with life-threatening toxicity, which limits its use to patients in relatively good health. Antitumor efficacy associated with rIL-2 therapy are hypothesized to be mediated by distinct types of cells that express structurally different forms of the IL-2 receptor. This hypothesis suggests that it might be possible to engineer an IL-2 variant addressing the risks associated with the therapeutic use of IL-2. In this article, we review the clinical experience with IL-2 and its analogs, the evidence that different IL-2 receptors may dissociate efficacy and toxicity, and describe the generation of a novel IL-2 variant with the potential for a superior therapeutic index.
 ...
PMID:Therapeutic enhancement of IL-2 through molecular design. 1236 61

A unique process has been developed to convert bituminous coal by controlled wet oxidation followed by base treatment to a water-soluble humate called oxihumate. The effects of oxihumate on the proliferative response of lymphocytes has been studied in vitro and ex vivo. Oxihumate increased the proliferative response of phytohaemagglutinin-stimulated human lymphocytes, from a concentration of 20 microg/ml and upwards. This response was even more striking in the case of lymphocytes from HIV-infected patients and was not limited to the in vitro setting since similar effects were observed ex vivo following administration of a non-toxic dosage of 4 g oxihumate per day to HIV-positive individuals for two weeks. Mechanistic studies revealed that stimulation of the proliferative response of lymphocytes by oxihumate is associated with an increased production of IL-2, as well as expression of the IL-2 receptor in the setting of decreased production of IL-10. Oxihumate therefore holds promise for the treatment of immunocompromized patients.
 ...
PMID:Investigation of the immunostimulatory properties of oxihumate. 1271 Jul 39

Propagation of R5 strains of HIV-1 on CD4 lymphocytes and macrophages requires expression of the CCR5 coreceptor on the cell surface. Individuals lacking CCR5 (CCR5 Delta 32 homozygous genotype) are phenotypically normal and resistant to infection with HIV-1. CCR5 expression on lymphocytes depends on signaling through the IL-2 receptor. By FACS analysis we demonstrate that rapamycin (RAPA), a drug that disrupts IL-2 receptor signaling, reduces CCR5 surface expression on T cells at concentrations as low as 1 nM. In addition, lower concentrations of RAPA (0.01 nM) were sufficient to reduce CCR5 surface expression on maturing monocytes. PCR analysis on peripheral blood mononuclear cells (PBMCs) showed that RAPA interfered with CCR5 expression at the transcriptional level. Reduced expression of CCR5 on PBMCs cultured in the presence of RAPA was associated with increased extracellular levels of macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta. In infectivity assays, RAPA suppressed the replication of R5 strains of HIV-1 both in PBMC and macrophage cultures. In total PBMC cultures, RAPA-mediated inhibition of CCR5-using strains of HIV-1 occurred at 0.01 nM, a concentration of drug that is approximately 103 times lower than therapeutic through levels of drug in renal transplant recipients. In addition, RAPA enhanced the antiviral activity of the CCR5 antagonist TAK-779. These results suggest that low concentrations of RAPA may have a role in both the treatment and prevention of HIV-1 infection.
 ...
PMID:Rapamycin causes down-regulation of CCR5 and accumulation of anti-HIV beta-chemokines: an approach to suppress R5 strains of HIV-1. 1291 36

Reconstitution of functional CD4(+) T cell responsiveness to in vitro stimuli is associated with continuous highly active antiretroviral therapy (HAART). Thirty-six antiretroviral naive patients received HAART over 16 weeks. Antigen-specific, mitogen and interleukin (IL)-2 induced lymphocyte proliferative responses and specific IL-2 and IL-4 production were assessed at each time-point, together with quantification of HIV-1 RNA load and lymphocyte populations. Reconstitution of recall responses was limited largely to persistent antigens such as Herpes simplex virus and Candida, rather than to HIV-1 or neo-antigens. Recall antigens, mitogens and IL-2-induced renewed responses were associated with in-vitro production of IL-2, but not IL-4. Differential responsiveness to low versus high concentration IL-2 stimulus increases in a stepwise manner, suggesting normalization of IL-2 receptor expression and improved functionality. These increases in in-vitro proliferative responses thus probably reflect short lived effector clones, driven by ongoing antigenic stimulus associated with persisting long-term organisms. In this context non-responsiveness to HIV-1 antigens suggests ongoing HIV-1 specific clonal T cell anergy.
 ...
PMID:Reconstitution of CD4+ T cell responses in HIV-1 infected individuals initiating highly active antiretroviral therapy (HAART) is associated with renewed interleukin-2 production and responsiveness. 1297 61


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>